Tumor microenvironment

Breast cancer is one of the most common female cancers and known to metastasize to brain.  It is acknowledged that brain prevents the entering of substances in the blood stream by blood-brain barrier (BBB) and only tiny materials can across the BBB.  In terms of size, cancer cells are too large to penetrate the BBB.  However, 30% of all women with metastatic breast cancer develop brain tumors.  Recently, many studies have suggested that the reciprocal interaction between cancer cells and environment is important for cancer metastasis.  Therefore, it is plausible that tumor microenvironment is involved in breast cancer brain metastasis.  Our research is to understand the role of Interface Zone in breast cancer brain metastasis.

Cancer Stem Cell

CSCs resemble cells that have undergone epithelial–mesenchymal transition (EMT) with regard to their invasiveness and motility. EMT, which is associated with a key step in tumor metastasis via induction of a highly invasive phenotype, has been intensely studied. And CSCs have been found to transiently acquire stem cell-like properties as a consequence of EMT. CSCs also are inherently chemoresistant and radioresistant. Recently, side population (SP) cells have been shown to express increased levels of MDR1 (multidrugresistance protein 1) and ABCG2 (ATP-binding cassette, sub-family G, member 2) transporters, which can extrude certain chemotherapeutic agents and have been implicated in drug resistance. Importantly, SP cells appear to be enriched in stem cells. Although this issue remains controversial, identifying and characterizing human ovarian CSCs would provide a critical step toward the identification of drugs with therapeutic efficacy against CSCs and the development of novel therapeutic strategies for the long-term control of cancer.

EMT process in primary cancer
EMT process in primary cancer

ChoiYP_04

Intratumoral heterogeneity model and cancer stem cells in human ovarian cancer

  • Heterogeneous populations may contain subpopulations with different phenotypic and genetic profiles. Among these are cancer stem cell-like cells (CSCs), a dynamically changing subpopulation of cancer-initiating cells (CICs) that arises due to the acquisition of malignant cellular transformations as part of a biological evolutionary process. Although, in theory, many tumors contain limited minority of CSCs, in practice, it is difficult to identify the cells that acquire the genetic/epigenetic alterations that lead to tumor initiation. As the name suggests, the CSC hypothesis describes a process driven by rare cellular components that display stem cell properties of self-renewal and differentiation: self-renewal promotes tumorigenesis, whereas differentiation contributes to the phenotypic heterogeneity of tumors.
  • The role of CSCs as adverse factors in ovarian cancer may reflect their suggested origin from aberrant CICs. Consistent with this, a subpopulation of cells isolated from mouse ovarian cancer cell lines and ascites of human ovarian cancer patients phenotypically resemble stem cells. CSCs are thought to be self-renewing and possess multipotency. This latter property enables CSCs to differentiate into diverse cells that display histologic heterogeneity and tumorigenicity, even in a subpopulation or a small minority of cells.

Tumor microenvironment
 – Double-edged sword

Tumor

Contemporary issue

  • Cellular/ soluble factors

– Balance score of pro-(MCP-1, IL-6, MMP) and anti-malignant (IP-10)   factors: 1.36~ 2.44 (Witz, IJCa 2003)

– No MECE

  • P-P interaction
  • Tumor heterogeneity vs. signal heterogeneity
  • Cross-talk (agonistic vs. antagonistic)

– TNF family

Proinflammatory cytokine as promalignant effect (since R. Virchow, 1863)

– TGF-β

> Inhibit normal mammary epithelail cells

> Enhance tumor cell invasion/mets:
 loss of anti-proliferative role
– mutation in TGFBR
– inhibition of SMAD pathway
– suppressing anti-tumor immune response
– augmenting angiogenesis

Tumor_02